qHBsAg trajectories with Peg-IFNα-2b add-on therapy in nucleos(t)ide analog-experienced HBeAg-positive chronic hepatitis B

HBsAg loss is the preferred endpoint for functional cure in chronic hepatitis B (CHB), but remains uncommon with finite treatment. Peg‑IFNα‑2b may increase HBsAg decline in selected patients, but small real‑world cohorts have limited HBsAg loss events. Binary endpoints do not capture on‑treatment qHBsAg dynamics, which are measured irregularly. This study characterised qHBsAg trajectories using LOESS in NA‑experienced patients receiving Peg‑IFNα‑2b add‑on therapy versus NAs alone.

Methods

Design: Real‑world, multicentre, prospective cohort study (2023–2025) in Shandong, China.

Participants: NA‑experienced, HBeAg‑positive CHB patients with ≥12 months continuous NA therapy and baseline HBsAg <3,000 IU/mL. Exclusions: HCV/HDV/HIV coinfection, other chronic liver diseases, NASH, HCC, telbivudine use.

Cohorts: 161 received Peg‑IFNα‑2b add‑on; 205 continued NAs alone. One‑to‑one propensity score matching (PSM) used age, sex, WBC, neutrophils, haemoglobin, platelets, and qHBsAg.

Analysis: Piecewise LOESS (span = 0.50) fitted before/after baseline. Kaplan‑Meier estimated cumulative HBsAg loss (≤0.05 IU/mL) with censoring at day 500.

Results

After PSM, 161 matched pairs were formed with balanced covariates. Median Peg‑IFNα‑2b duration was 315 days (IQR 172–350); 64/161 (39.8%) received ≥48 weeks.

qHBsAg trajectories: Peg‑IFNα‑2b add‑on showed rapid decline after initiation, reaching nadir at ~10–12 months (2.48 log10 IU/mL; 95% CI 2.38–2.61), followed by modest rebound. NAs‑alone showed minimal change. By month 10, 81/161 (50.3%) had discontinued Peg‑IFNα‑2b, coinciding with the rebound.

HBsAg loss: Within 500 days, 3 patients in the add‑on group achieved HBsAg ≤0.05 IU/mL versus none in NAs‑alone. Kaplan‑Meier showed a trend toward higher cumulative HBsAg loss (log‑rank P = 0.06).

Exploratory: WBC and PLT declined early after Peg‑IFNα‑2b then recovered. qHBeAg declined more rapidly in the add‑on group during the first six months.

Discussion

Peg‑IFNα‑2b add‑on was associated with early qHBsAg decline followed by modest rebound, whereas NAs alone showed minimal change. The rebound may reflect attenuation of interferon‑induced transcriptional repression, allowing partial restoration of cccDNA‑driven transcription. Mechanistically, Peg‑IFNα represses HBV cccDNA via HDAC3‑associated histone modifications and enhances NK‑cell‑mediated inhibition of regulatory T cells.

Limitations: Observational study with non‑randomised control; residual confounding possible. Baseline ALT, prior NA duration, adherence, and HBV genotype were incompletely recorded. Selected population limits generalisability. Variable treatment duration may influence trajectory shape.

Conclusions

Among NA‑experienced, HBeAg‑positive CHB patients with baseline HBsAg <3,000 IU/mL, Peg‑IFNα‑2b add‑on therapy was associated with rapid early qHBsAg decline followed by modest rebound, whereas NAs alone showed minimal change. Although between‑group difference in HBsAg loss did not reach statistical significance, a trend toward higher cumulative HBsAg loss was observed in the add‑on group. LOESS trajectories offer an intuitive way to visualise qHBsAg dynamics in small real‑world cohorts with irregular sampling and few endpoint events.

Full text

https://www.xiahepublishing.com/2310-8819/JCTH-2026-00175

The study was recently published in the Journal of Clinical and Translational Hepatology.

The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study’s novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.

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